This application for a mentored clinical scientist development award is designed to offer the principal investigator (P.I.), Dr. Rumbaut, the necessary research experience and skills to develop into an independent investigator. The P.I. is an Assistant Professor in the Pulmonary/Critical Care Division of the University of Missouri. His clinical and teaching responsibilities in the Division will comprise 20% of his full time effort. The Division has an active clinical research program, with an emphasis on two diseases associated with major alterations in microvascular function, sepsis and acute respiratory distress syndrome (ARDS). The P.I. is enrolled in a doctoral program in Physiology, under the mentorship and guidance of Dr. Virginia Huxley. The environment for cardiovascular research and cellular transport is excellent, as 85% of the physiology department works in this area. The research plan will examine the role of nitric oxide (NO) on regulation of microvascular permeability to water and solutes. Microvascular permeability is a dynamic process which regulates water and solute exchange, and may be increased or decreased from basal levels by a variety of stimuli. NO is an endothelial-derived relaxing factor which participates in regulation of local blood flow and pressure. The influence of NO on regulation of microvascular permeability is unclear, as both increases and decreases in exchange by NO synthase inhibitors have been described. The central hypothesis of this application is that basal NO release regulates microvascular permeability to water and solutes. This application will combine four methodologies of assessment of microvascular exchange in in vivo rat mesenteric venules, to test two hypotheses: 1) Basal release of nitric oxide influences basal venular permeability to water and solutes, and 2) Circulating humoral and/or cellular factors account for the increases in vascular protein leakage by NOS inhibition. The long term goal of this research is to elucidate the mechanisms by which microvascular permeability is regulated under physiologic conditions. This will provide insight into the pathophysiology of diseases which are associated with alterations in microvascular permeability, such as sepsis and ARDS, and will likely yield a more rational pharmacological approach to the microvascular dysfunction present in these and other disease entities. (End of Abstract)